CA2126200C - Prolamine coatings for taste-masking orally-administrable medicaments - Google Patents
Prolamine coatings for taste-masking orally-administrable medicamentsInfo
- Publication number
- CA2126200C CA2126200C CA002126200A CA2126200A CA2126200C CA 2126200 C CA2126200 C CA 2126200C CA 002126200 A CA002126200 A CA 002126200A CA 2126200 A CA2126200 A CA 2126200A CA 2126200 C CA2126200 C CA 2126200C
- Authority
- CA
- Canada
- Prior art keywords
- nutritional
- prolamine
- active agent
- agent
- weight
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5052—Proteins, e.g. albumin
Abstract
Prolamine fractions of grain proteins, applied in weight ratios of 5 to 100 % relative to the active agent being coated, effectively prevent the partitioning of water-soluble or water-insoluble drugs at neutral pH's in the mouth and thereby mask the taste of orally-administered drugs, which normally have a bitter taste, without sacrificing bioavailability. Zein, gliadin or a mixture thereof, particularly in combination with between 2.5 and 15 % of water-insoluble vegetable source oil or wax capable of plasticizing the prolamine fraction, when applied to particles, granules, tablets or other forms of drugs or nutritionals, to an effective thickness of about 1 to about 35 micrometers, in order to encapsulate and prevent release of an orally-administered pharmaceutical or nutritional in a suspension or chewable dosage form until such medicament reaches the stomach.
Description
W0 93rl2771 2 ~ ~ 6 ~ U O Pcr/usg~J~
tPROLAMIN~ (:~Q~TINGS FOE? TASTE-MASKING ORALLY-ADM~ISl-RABLE
~DI(~MENTS
TECHNICAL ~IELD
The pr~s~n~ inven~on relates to o~ o~~ ions which ef~ vely mask the undesirable ~stes of drags, such as an~bio~s or ben7 xli~ es, and n~ n~
suchasdietaryfibe~oraminoacidsupple ~ ndo~hersimilar~h~ Ac~ or nllh;tit)n~ls ~ bi~er or od~ nd~i~ble ~stes. ~ pafdcular, d~ inven~on rela~es ~o ~ste-m~ d m~dic~,~.F..-I~ c~rable Of being chewed or swallowed wil~o~L
prQr~ n~ a bi~ taste in ~e mou~L .
BACK~ROUND OF I~ INVENTION
n~ on o~~h~nn~entic~t~ and ~ ;c~na~$ is one oI dle most popular m~tho~ls oP deliveIy of such be- ief~ agents. Chewable or ~us~e~Sion dosage ~onns are ~ d r~ute o~ such o~ ~ L~ ~on for both children arld dults who haYe difficulty swallo~g capsules o~ table~ q,th p~lat~ y bC~g an extremely ~p~ actor in ~ ;n~ ese dosage f~ms in order to ~ the lik~ .t the ~ipjent wil e yh~ r~ tiG~l or ~
Because of the strong, unrle-~nt taste o~many r ~ n~r~, flavo~gs, ei~her ~one or in cQ~h~ and o~er addi~ves, haYe been employed to improve taste and p~ y, The fo~ n of a pleasant-tas~ng and palata~le product th~ough ~}e 501e use ~f fla~r~ings, s~ .n~ and addi~res, however, has been uns~lccGs~l ;n many m~Aic~ which have a par~icula~ly bitter ~ste, such as ~e macrolide ~amily of an~ibiotics, in par~cular tlyl on~yein and cl~i~ ycin. Attem~ts have been made to fo~nulate these ~tibiotics Lnto sJ-spension dosage fo~ns ~r into taste-m~cked chewable tablets using known coating or enc~rs~ on processes with very limited su~cess.
Tsutomu, in Japanese Patent Application 45-1~759, published November 1, 19Ç7~ cl~ims phannaceu~cal compositions co~i.cting of zein and hydroxypr~pylmethylcelllllose (HPMC) in coating tablets to mask taste and odor.
The application employs the high molecular weight polymeric H~C component (exe,mpli~led at levels of 10% and above) for its film-foIming proper~es, in a coating used to prevent the disintegra~on of Vitamin C as measured by tempera~u~e and time.
Pescetti, in U.S~ Patent 3,939,259, issued Feb. 17, 1976, employed prolamine from corn grain protein (i.e., zein) with approximately an equal level of shellac and a lesser amount of ethylcellulose, to coat digitoxin particles, but did so to achieve a sustained-release effect. Since the incorporation of ethylcellulose may interfere with absorption of the active agent in a timely manner, its incorporation into the present invention for an immediately-available medicament would be unsuitable.
Cea, in U.S. Patent 4,384,004, issued on May 17, 1983, discloses the encapsulation of the artificial sweetener, L-aspartyl-L-phenylalanine methyl ester (APM), with additional coating materials, which may include zein, for increasing shelf life stability.
In comparison with these known formulations, the present invention provides a taste-masked product in a chewable or nonchewable dosage form or suspension, with immediate bioavailability. Additionally, the taste-masking ability of the present invention is due solely to the prolamine fraction of grain, with only minor levels of a low-to-moderate molecular weight plasticizer needed to form the film coating.
SummarY of the Invention The present invention is directed to an orally-administerable medicament comprising (a) a core-mixture of a pharmaceutically-active agent or nutritional, having a surface and (b) an outer polymeric coating layer comprising a prolamine fraction of grain protein, preferably zein or gliadin or mixtures thereof, and a low-to-moderate weight plasticizing agent for plasticizing said prolamine, preferably a nonpolymeric agent, for example, a vegetable source water-insoluble oil or wax and wherein the ratio of prolamine to plasticizing agent is from 40:1 to 20:3.
The present invention further relates to a medicament wherein the ratio of the pharmaceutically-effective agent or nutritional to the prolamine fraction is 20:1 to 1:1, and the outer layer is from about 1 to about 35 micrometers thick. In particular, the invention comprises taste-masked medicaments capable of being incorporate into a suspension or chewable dosage form without producing a bitter taste.
In the liquid suspension the taste of the active agent or nutritional is masked by the coating layer substantially preventing dispersion of such active agent or nutritional into the suspension while being readily disintegrated by human gastric juices such that the active agent or nutritional is released.
Brief DescriPtion of the Drawinqs Figure 1 is a graph of the plasma concentration of clarithromycin versus time of both the zein-coated clarithromycin suspension and the clarithromycin tablet reference, administered at 125 mg of clarithromycin activity per dog.
~vo 93/12771 212 6 2 0 Q P~/US92~11011 Figu~ 2 is is a ~ph of the ~ elllcss (on a sc~ of O to 3, where O represents no bitt~rn~ss and a 3 ~ s~.lts a s~ng bi~l~.n~,s) observed for a cl~itlL.~ cin conce.n~atiorl in solutîon.
Figure 3 is ~ ~ph of the l,~ ss obs~ved for ~e form~ n of ~eîn-coa~d cla~ "ycin p~cles in ~ o,,s en~n~ for bo~ ally-~ us~Gi~iou ~IDay ~) and one which was ~ d and allowed to stand for 7d~ys, as a fi~n-.tion o~ ~dme a~t~r ~s~ng.
~etaile~ Des~ îon of d-e Imen~on:
The pnesent inven~on r~lates to dle use of an oute~ polymeric coa~ng laye~ tO
effec~vely ~te~ hA, .,~ y~ ive age~ n~l~iti( n~ls which have bitt~r or od~erwise undesirable ~astes. I~e fo~ s o~ dle present inven~on c~ ise ~a? a cor~ o~ a ~llA.in~,~ lly-ac~vc agen~ ;Qt~ as well as ~ tent~, fllers o~ inac~ve ingredieIlts nece~s~ or ~e ~orrn~ n of the ph~ c~ i~ cor~, arld (b) an oute~ polym~c eoa~g layer G~m~.~ing a p~ min~ ~on of ~u~ S and a low-t~mo~e~?te m~70c~ r welght pl~sti~Yin~ agent i~or said P~OIAm;ne.
The PrO~m;nf~. fi~ n 1S PUIi~d ~m ~rn or wheat and in~ l~ldes zeîn or gliadin ~r ~ s thereo~, but prefe~a~ly is zeirl ~e p~olamine fi~ n Of COrn) which has been punfied to b~tw~en 8~96~, most ~ ndally, 92-96%.
Atl~it;on~lly, the pro~ ines present in the p~l~d coa~ng forrntll~tion ~11 b~
present ~ a solu~on consis~ng of 9~% ~ood gracle ethanol and 10% distîll~ water at a ~fc~l~l level o~ bet~een 5% an~ 20% prol~mine.
Ttle pl~stîci7in~ agent which îs ~c~l~Lially present on a we;~ht basîs between 2.5% and 25% rela~ive to ~e prol~mine fi~chon~ is a water-insolub1e vegetable source oil or wax, an~ includes, but is not limited to, f~tty acids of chain len~s SLY to twen~r-h vo (both saturated and unsa~ ted carbon chains a*e equa11ysuit~ble), nonionic cellulosic polymers (e.g., hydroxypropyl cellulose and hydroxyethyl cellulose), and polyv~nylpyrrolidone of molecular weight range 30,000 to 400,00a daltons. Most preferred plasticizers are fatty acids of chain lengt~s six-to-eighteen which are present on a weight basis of between ~.5 and lS %.
.
The optimum thickness of the coating material is between about 1 and about 35 microns to the core of the pharmaceutically-active agent or nutritional. The preferred level of coating consists of from about 5% to about 100% of applied film polymeric coating, wherein the major constituent is the prolamine fraction of grain protein(with the percent representing the weight of film coating relative to the initial weight of the core of the medicament). The most preferred level of coating is between 45 to 75% weight of coating to weight of the medicament core.
The preparation of the formulation may be accomplished by a variety of coating techniques known in the art, including fluidized bed coating, coacervation (i.e., microencapsulation), or a combination thereof as disclosed by Cea et al, in U.S. Patent 4,384,004.
Preferably, wet granulation techniques may be employed to form the medicament core, and fluidized bed coating, with a Wurster column insert may preferentially be employed to apply the coating, as described by Mehta et al, in U.S.
Patent 4,800,087.
The preferred method for preparing the pharma-ceutically-active core is to co-mix the active agent with a portion of inactive binder consisting of polyvinyl-pyrrolidone (PovidoneTM made by International Specialty Chemicals Corp.) of a molecular weight range of 30,000 to 400,000 in a weight to weight basis of 5% to 65% of the active ingredient. Alternative granulating agents capable of assisting in the formation of a particle containing the active ingredient include, hydroxypropyl-cellulose (KlucelTM, Hercules Corporation), hydroxy-propylmethyl cellulose, (MethocelTM, Dow Chemical Corp.), Pregelatinized Starch, (Colorcon, Inc.) or any other material suitable for use as a binding agent for the formation of particles capable of being utilized as pharmaceutically active cores. After blending, a sufficient portion of water or food grade ethanol is added to wet mass the mixture into a wet granulation.
This material may be either oven-dried under mild heat or dried in a fluidized bed air-drying system, which is capable of performing the task in a more efficient, less time-consuming fashion. The particles are then dried to a specified level of dryness (based on weight loss measurements) and milled to produce a small particle size range. These particles may then be sieved to collect the fraction of particles of a particular size range for subsequent coating. Alternate methods for preparing particles are equally useful at creating particles of a suitable size range.
A wide range of medicaments and nutritionals are suitable for formulation in the present invention. Such medicaments and nutritionals include antibiotics, prefer-ably macrolide antibiotics, and other antibacterial agents, analgesics, antihistamines, decongestants, anti-inflammatory agents, hypnotics, sedatives, tranquilizers, vitamins, enzymes, nutritional supplements, dietary fibers, amino acids, hormones and the like. Those with an especially bitter taste, such as macrolide antibiotics, specifically erythromycin and clarithro-mycin, are particularly suited for the present invention.
The formulation of the present invention may be incorporated into a variety of pharmaceutical and nutritional products, including pharmaceutical suspensions, pediatric infant formulas, and nutritional supplements.
4a Example 1 A. Preparation of Clarithromycin :
Polyvinylpyrrolidone Particles To a pharmaceutically-active core consisting of clarithromycin, 90%, and polyvinylpyrrolidone (Povidone, K-30, ISP Corp.), 10%, a sufficient amount of food grade ethanol was added with mixing to form a wet mass. The wet granulation was then dried in an oven (between 50~
and 60~C) until the loss on drying (LOD) was less than 1%. These particles were then ground to a smaller size and the fraction of particles between 177 and 420 microns collected (40-80 mesh fraction).
B. Preparation of Zein-Coated Clarithromycin :
Polyvinylpyrrolidone Particles To 4 kg of the Clarithromycin : polyvinylpyrrolidone particles, prepared as described above, was applied 2.8 kg of solids contained in a coating formulation consisting of zein (93%) and medium chain triglycerides (7%). This coating formula was dispersed in a mixture of 90% food grade ethanol and 10% distilled water to a level of 10.75% solids (prolamine fraction and medium-chain triglycerides), in this cosolvent mixture. The coating was performed in a Glatt GPCG-5 bottom spray particle coater with a fluidized bed and a Wurster column. Inlet temperature was maintained between 39~ and 45~C, with the exhaust temperature between 26~ and 29~C, and the automization pressure on the spray nozzle was maintained between a range of 26 to 30 pounds per square inch. The flow rate of application of coating liquid to the particles was maintained in the range of 10 to 15 mL per minute.
WO 93112771 PCT/US9~/~10~
? 1~ fi 2 ~ ~ Fx~m~le 2 Pissolution of Zein-(~o~ted Cl~ J-lIy~in: P~lyvinylp~rolidone P~çles ~s a Function of ~.
Ihe zein-coa~ed Cl&~ ycin: pol~nylpy~rolidone particles, ~ d as descnbed in Example lA~were tested using a ~ sollltion a~a~t-ls to evaluate the percent of ac~ve ingredient released into a 900 mL ~lis~ol~tion ba~ of pH-buffered solution over a two hour pe iod. A dose of 125 m~ of c~ o~ ac~ was was used as a r~prese.nt~tive dose ~d f~ soll~tion was tes~ed at pH 2.0, 5~û, and 6.8.
S~mrles werc ~dldrawn at 3Q 60, 90 and 120 ~ es. ~Ihe results, as shown ~y Table I9 below, in~ te no ac~ve drug was released at pH 6~8~ Rapid rclease o~ ~eactiYc drug was observed at p~ 2Ø
l'S~ble 1 pissolution of Zein-Coated Cla~ cin: PolyYinylpylToli~one Par~icles as a ~unction of ~H.l Time (min) % DrugRele~e~ :
p~I 2 pH 5 .~ pH 6~8 80.8 (8.1)2 35.9 (22.3) nd3 90.9 ~3.0) 52.9 ~13.2) nd ~ 94.7 (4.1) 62.4 (8.5) nd 12Q 96~3 (2~ 69~4 (1t~7) nd 1~ Par~cles coated wi~h 70% weight eoa~ng to weight of particle~
tPROLAMIN~ (:~Q~TINGS FOE? TASTE-MASKING ORALLY-ADM~ISl-RABLE
~DI(~MENTS
TECHNICAL ~IELD
The pr~s~n~ inven~on relates to o~ o~~ ions which ef~ vely mask the undesirable ~stes of drags, such as an~bio~s or ben7 xli~ es, and n~ n~
suchasdietaryfibe~oraminoacidsupple ~ ndo~hersimilar~h~ Ac~ or nllh;tit)n~ls ~ bi~er or od~ nd~i~ble ~stes. ~ pafdcular, d~ inven~on rela~es ~o ~ste-m~ d m~dic~,~.F..-I~ c~rable Of being chewed or swallowed wil~o~L
prQr~ n~ a bi~ taste in ~e mou~L .
BACK~ROUND OF I~ INVENTION
n~ on o~~h~nn~entic~t~ and ~ ;c~na~$ is one oI dle most popular m~tho~ls oP deliveIy of such be- ief~ agents. Chewable or ~us~e~Sion dosage ~onns are ~ d r~ute o~ such o~ ~ L~ ~on for both children arld dults who haYe difficulty swallo~g capsules o~ table~ q,th p~lat~ y bC~g an extremely ~p~ actor in ~ ;n~ ese dosage f~ms in order to ~ the lik~ .t the ~ipjent wil e yh~ r~ tiG~l or ~
Because of the strong, unrle-~nt taste o~many r ~ n~r~, flavo~gs, ei~her ~one or in cQ~h~ and o~er addi~ves, haYe been employed to improve taste and p~ y, The fo~ n of a pleasant-tas~ng and palata~le product th~ough ~}e 501e use ~f fla~r~ings, s~ .n~ and addi~res, however, has been uns~lccGs~l ;n many m~Aic~ which have a par~icula~ly bitter ~ste, such as ~e macrolide ~amily of an~ibiotics, in par~cular tlyl on~yein and cl~i~ ycin. Attem~ts have been made to fo~nulate these ~tibiotics Lnto sJ-spension dosage fo~ns ~r into taste-m~cked chewable tablets using known coating or enc~rs~ on processes with very limited su~cess.
Tsutomu, in Japanese Patent Application 45-1~759, published November 1, 19Ç7~ cl~ims phannaceu~cal compositions co~i.cting of zein and hydroxypr~pylmethylcelllllose (HPMC) in coating tablets to mask taste and odor.
The application employs the high molecular weight polymeric H~C component (exe,mpli~led at levels of 10% and above) for its film-foIming proper~es, in a coating used to prevent the disintegra~on of Vitamin C as measured by tempera~u~e and time.
Pescetti, in U.S~ Patent 3,939,259, issued Feb. 17, 1976, employed prolamine from corn grain protein (i.e., zein) with approximately an equal level of shellac and a lesser amount of ethylcellulose, to coat digitoxin particles, but did so to achieve a sustained-release effect. Since the incorporation of ethylcellulose may interfere with absorption of the active agent in a timely manner, its incorporation into the present invention for an immediately-available medicament would be unsuitable.
Cea, in U.S. Patent 4,384,004, issued on May 17, 1983, discloses the encapsulation of the artificial sweetener, L-aspartyl-L-phenylalanine methyl ester (APM), with additional coating materials, which may include zein, for increasing shelf life stability.
In comparison with these known formulations, the present invention provides a taste-masked product in a chewable or nonchewable dosage form or suspension, with immediate bioavailability. Additionally, the taste-masking ability of the present invention is due solely to the prolamine fraction of grain, with only minor levels of a low-to-moderate molecular weight plasticizer needed to form the film coating.
SummarY of the Invention The present invention is directed to an orally-administerable medicament comprising (a) a core-mixture of a pharmaceutically-active agent or nutritional, having a surface and (b) an outer polymeric coating layer comprising a prolamine fraction of grain protein, preferably zein or gliadin or mixtures thereof, and a low-to-moderate weight plasticizing agent for plasticizing said prolamine, preferably a nonpolymeric agent, for example, a vegetable source water-insoluble oil or wax and wherein the ratio of prolamine to plasticizing agent is from 40:1 to 20:3.
The present invention further relates to a medicament wherein the ratio of the pharmaceutically-effective agent or nutritional to the prolamine fraction is 20:1 to 1:1, and the outer layer is from about 1 to about 35 micrometers thick. In particular, the invention comprises taste-masked medicaments capable of being incorporate into a suspension or chewable dosage form without producing a bitter taste.
In the liquid suspension the taste of the active agent or nutritional is masked by the coating layer substantially preventing dispersion of such active agent or nutritional into the suspension while being readily disintegrated by human gastric juices such that the active agent or nutritional is released.
Brief DescriPtion of the Drawinqs Figure 1 is a graph of the plasma concentration of clarithromycin versus time of both the zein-coated clarithromycin suspension and the clarithromycin tablet reference, administered at 125 mg of clarithromycin activity per dog.
~vo 93/12771 212 6 2 0 Q P~/US92~11011 Figu~ 2 is is a ~ph of the ~ elllcss (on a sc~ of O to 3, where O represents no bitt~rn~ss and a 3 ~ s~.lts a s~ng bi~l~.n~,s) observed for a cl~itlL.~ cin conce.n~atiorl in solutîon.
Figure 3 is ~ ~ph of the l,~ ss obs~ved for ~e form~ n of ~eîn-coa~d cla~ "ycin p~cles in ~ o,,s en~n~ for bo~ ally-~ us~Gi~iou ~IDay ~) and one which was ~ d and allowed to stand for 7d~ys, as a fi~n-.tion o~ ~dme a~t~r ~s~ng.
~etaile~ Des~ îon of d-e Imen~on:
The pnesent inven~on r~lates to dle use of an oute~ polymeric coa~ng laye~ tO
effec~vely ~te~ hA, .,~ y~ ive age~ n~l~iti( n~ls which have bitt~r or od~erwise undesirable ~astes. I~e fo~ s o~ dle present inven~on c~ ise ~a? a cor~ o~ a ~llA.in~,~ lly-ac~vc agen~ ;Qt~ as well as ~ tent~, fllers o~ inac~ve ingredieIlts nece~s~ or ~e ~orrn~ n of the ph~ c~ i~ cor~, arld (b) an oute~ polym~c eoa~g layer G~m~.~ing a p~ min~ ~on of ~u~ S and a low-t~mo~e~?te m~70c~ r welght pl~sti~Yin~ agent i~or said P~OIAm;ne.
The PrO~m;nf~. fi~ n 1S PUIi~d ~m ~rn or wheat and in~ l~ldes zeîn or gliadin ~r ~ s thereo~, but prefe~a~ly is zeirl ~e p~olamine fi~ n Of COrn) which has been punfied to b~tw~en 8~96~, most ~ ndally, 92-96%.
Atl~it;on~lly, the pro~ ines present in the p~l~d coa~ng forrntll~tion ~11 b~
present ~ a solu~on consis~ng of 9~% ~ood gracle ethanol and 10% distîll~ water at a ~fc~l~l level o~ bet~een 5% an~ 20% prol~mine.
Ttle pl~stîci7in~ agent which îs ~c~l~Lially present on a we;~ht basîs between 2.5% and 25% rela~ive to ~e prol~mine fi~chon~ is a water-insolub1e vegetable source oil or wax, an~ includes, but is not limited to, f~tty acids of chain len~s SLY to twen~r-h vo (both saturated and unsa~ ted carbon chains a*e equa11ysuit~ble), nonionic cellulosic polymers (e.g., hydroxypropyl cellulose and hydroxyethyl cellulose), and polyv~nylpyrrolidone of molecular weight range 30,000 to 400,00a daltons. Most preferred plasticizers are fatty acids of chain lengt~s six-to-eighteen which are present on a weight basis of between ~.5 and lS %.
.
The optimum thickness of the coating material is between about 1 and about 35 microns to the core of the pharmaceutically-active agent or nutritional. The preferred level of coating consists of from about 5% to about 100% of applied film polymeric coating, wherein the major constituent is the prolamine fraction of grain protein(with the percent representing the weight of film coating relative to the initial weight of the core of the medicament). The most preferred level of coating is between 45 to 75% weight of coating to weight of the medicament core.
The preparation of the formulation may be accomplished by a variety of coating techniques known in the art, including fluidized bed coating, coacervation (i.e., microencapsulation), or a combination thereof as disclosed by Cea et al, in U.S. Patent 4,384,004.
Preferably, wet granulation techniques may be employed to form the medicament core, and fluidized bed coating, with a Wurster column insert may preferentially be employed to apply the coating, as described by Mehta et al, in U.S.
Patent 4,800,087.
The preferred method for preparing the pharma-ceutically-active core is to co-mix the active agent with a portion of inactive binder consisting of polyvinyl-pyrrolidone (PovidoneTM made by International Specialty Chemicals Corp.) of a molecular weight range of 30,000 to 400,000 in a weight to weight basis of 5% to 65% of the active ingredient. Alternative granulating agents capable of assisting in the formation of a particle containing the active ingredient include, hydroxypropyl-cellulose (KlucelTM, Hercules Corporation), hydroxy-propylmethyl cellulose, (MethocelTM, Dow Chemical Corp.), Pregelatinized Starch, (Colorcon, Inc.) or any other material suitable for use as a binding agent for the formation of particles capable of being utilized as pharmaceutically active cores. After blending, a sufficient portion of water or food grade ethanol is added to wet mass the mixture into a wet granulation.
This material may be either oven-dried under mild heat or dried in a fluidized bed air-drying system, which is capable of performing the task in a more efficient, less time-consuming fashion. The particles are then dried to a specified level of dryness (based on weight loss measurements) and milled to produce a small particle size range. These particles may then be sieved to collect the fraction of particles of a particular size range for subsequent coating. Alternate methods for preparing particles are equally useful at creating particles of a suitable size range.
A wide range of medicaments and nutritionals are suitable for formulation in the present invention. Such medicaments and nutritionals include antibiotics, prefer-ably macrolide antibiotics, and other antibacterial agents, analgesics, antihistamines, decongestants, anti-inflammatory agents, hypnotics, sedatives, tranquilizers, vitamins, enzymes, nutritional supplements, dietary fibers, amino acids, hormones and the like. Those with an especially bitter taste, such as macrolide antibiotics, specifically erythromycin and clarithro-mycin, are particularly suited for the present invention.
The formulation of the present invention may be incorporated into a variety of pharmaceutical and nutritional products, including pharmaceutical suspensions, pediatric infant formulas, and nutritional supplements.
4a Example 1 A. Preparation of Clarithromycin :
Polyvinylpyrrolidone Particles To a pharmaceutically-active core consisting of clarithromycin, 90%, and polyvinylpyrrolidone (Povidone, K-30, ISP Corp.), 10%, a sufficient amount of food grade ethanol was added with mixing to form a wet mass. The wet granulation was then dried in an oven (between 50~
and 60~C) until the loss on drying (LOD) was less than 1%. These particles were then ground to a smaller size and the fraction of particles between 177 and 420 microns collected (40-80 mesh fraction).
B. Preparation of Zein-Coated Clarithromycin :
Polyvinylpyrrolidone Particles To 4 kg of the Clarithromycin : polyvinylpyrrolidone particles, prepared as described above, was applied 2.8 kg of solids contained in a coating formulation consisting of zein (93%) and medium chain triglycerides (7%). This coating formula was dispersed in a mixture of 90% food grade ethanol and 10% distilled water to a level of 10.75% solids (prolamine fraction and medium-chain triglycerides), in this cosolvent mixture. The coating was performed in a Glatt GPCG-5 bottom spray particle coater with a fluidized bed and a Wurster column. Inlet temperature was maintained between 39~ and 45~C, with the exhaust temperature between 26~ and 29~C, and the automization pressure on the spray nozzle was maintained between a range of 26 to 30 pounds per square inch. The flow rate of application of coating liquid to the particles was maintained in the range of 10 to 15 mL per minute.
WO 93112771 PCT/US9~/~10~
? 1~ fi 2 ~ ~ Fx~m~le 2 Pissolution of Zein-(~o~ted Cl~ J-lIy~in: P~lyvinylp~rolidone P~çles ~s a Function of ~.
Ihe zein-coa~ed Cl&~ ycin: pol~nylpy~rolidone particles, ~ d as descnbed in Example lA~were tested using a ~ sollltion a~a~t-ls to evaluate the percent of ac~ve ingredient released into a 900 mL ~lis~ol~tion ba~ of pH-buffered solution over a two hour pe iod. A dose of 125 m~ of c~ o~ ac~ was was used as a r~prese.nt~tive dose ~d f~ soll~tion was tes~ed at pH 2.0, 5~û, and 6.8.
S~mrles werc ~dldrawn at 3Q 60, 90 and 120 ~ es. ~Ihe results, as shown ~y Table I9 below, in~ te no ac~ve drug was released at pH 6~8~ Rapid rclease o~ ~eactiYc drug was observed at p~ 2Ø
l'S~ble 1 pissolution of Zein-Coated Cla~ cin: PolyYinylpylToli~one Par~icles as a ~unction of ~H.l Time (min) % DrugRele~e~ :
p~I 2 pH 5 .~ pH 6~8 80.8 (8.1)2 35.9 (22.3) nd3 90.9 ~3.0) 52.9 ~13.2) nd ~ 94.7 (4.1) 62.4 (8.5) nd 12Q 96~3 (2~ 69~4 (1t~7) nd 1~ Par~cles coated wi~h 70% weight eoa~ng to weight of particle~
2. A~erage (+S~D.), n=3.
3. No detec~ble response.
Example 3 Release of Zein-Coate~ Clarithromycin: PolvvinylpvlTolidone Pa~ticles as a Function of Time.
To a solu~on in which sodium bicarbonate (50 mg/5 cc) was dissolved, 125 mg/5 cc of claIi~hrornycin ac~vity (accounting for potency of the active agent and ~he particles), was added, shaken and observed for release of active agent as a func~ion of ~ 12 6 2 n PC~/US92/11011 ~0 93/12771 v ~I
time. Samples were withdrawn, filtered, and measured at 0,4, 24, 72, and 196 hours. ~e samples were filte~ed to remove the suspended partic~es and dle clear fils~e was analyzed for cl~illu~ ycin conten~ The resul~s, as shown in Table 2, below, inslit.~te th~t ve~y low levels of ac~ve drug are released over prolonged periods of ~me.
T~ble 7 Re~ease of Zeitl-CQated C~ wnlyci~ 'olyvillyl~ lidone Pardcles as a l;unction ~Time.
Tim~ (hours) ~0n (~cg/ml~ Pe~en~ ~o o ~0 ' 0 4 ~50 0.24 24 99 0.40 72 118 0.47 19~ 102 0.4 lExamD1e 4 Formulation ~Zein-Coated Clan~ yc;r Zein~oated c~in, com~ iO~o coa~ng was form follows:
~;C~t Amount per dose (5cc) Coa~d cl~i~ ycin260. mg (125 mg activi~) Sucrose 3000. mg ~nth~n gum 73 mg Silica(:3el 10.0 mg Pot~si~ orbate 20.0 mg Bubble Gum Flavor 14.0 mg Sodi~m Bicarbonate 50.0 mg To~als: 3361.5 mg/5 mL ~lnal volume WO 93/12771 PCI /US92/1 101~-2 i~ 6 ~ ~xam~le 5 Bioavaila~ility of Zein-Coated Cl~stlslulsly~;in The bioav~ fy of zein~oated c~ cin~ form~ eA as described in F.~m~le 4, was con~lctç~l in a beagle dog model using an single s~ss~ver design.The study co~d siIlgle dose immPAi~te release tablets c~ 125 mg of daLi~ ~yci~ acti~ to the microc~rslllçs of cl~ill ycin ~ed as ~ in Example 1, abo~e, and ~orm~ e~l as descn~ in PY~mrle 4, above. Th~ r~leasc of cla~ .;in was ~le ~-onci~ ~s~l by a 5~DsS over ~ - of the bioaY~ bili~y Of dle fo~ in a beagle dog model ~ ~ to a ~abletl~~~ ce ~r~ same.
The cross over design allowed d e same d~gs to receive bodl ~ ~~n coa~ed cla~ ~y~ s~ olt as well as dle ~ y~ er~ abl~ ~f the same dose ~125 mg cl~i~ n~eil~ ac~ty)O The results, illus~ d in ~e 1, non~ e ~at ~e ~in~oated cl~;~on~Ll s~.sp~n~ioll did not rele~e ~he cla~ e suspension ~as shown by a ~ep ~,s~r~ e suspension in Example 3, Table 2), but rapidly released dle ac~ve drug in the ga~oi~ siil-~l trac~ of dle dog for eql~ivalent absorption to that ~f dle l~;f~ ce table~
Example 6 Flavor Evalua~ion of Zein-Coated Cl~ ycin Colllp~ te flavor ev~ Qn no~ng characteris~cs of bitterness of ~le particle~coa~ed cla~ ycin and cl~;~ ycin in solu~on was con~ c~3 lhe fo~ula~on used was tha~ descnbed in Example 4~ and was compared with ~: cl~i~i,ulllycin in solu~on as a re~erence standard for the level of bitterness observed for ~e s~np1es. The study was conducted using trained flavor specialis~ whv :~
standardize their palate with ~e use of references which were, in this case, dlesolutions of cld~ ycin. The study CC~n~i~ts of swirling a dose of the matenal, -:
solution or suspended forrnulation, in the mouth and th~n ~ing bittemess, relative to standards, as a ~nc~on of time after tasdng it. The period of time after tasting is evaluated in the event that particles remain or get lodged in the oral cavity be~ore being removed by salivaly secre~ions.
The dose response for the clarithromycin in solu~on can be seen in Figure 2 and the corresponding level of response ~or the suspension is shown ;n Figure 3, as a '~'0 93~1~771 2 1 2 6 2 0 0 37C~/US92tl 1~
func~ion of ~ime after tasting, to demonstrate the lack of bitterness of this forrnulation.
Figure 3 thus shows that levels of free clarithromycin available ~or interaction with easte buds are below 15 ppm even after 7 days in suspension,dlus demonstrating the taste rnz~kin~ abili,~y ~f the zein coa~ng ~r an example of a very bit:ter ph~ e~ ally-ac~ve agent.
Al~ough ~e invention has been exemplilq~d in ~ecirlc Inr~i~r~1iQns~ the details are no~ to be construed as limit~ion~ r it ~ be ay~ar~nt daat va~ious esluivalents, changes and .nc~ c~1~0ns may be e~loyed without d~parting from the~iIit and sco~e the~o~, it being un~le~stood ~at such ~quivalen~ ts are int~.n~1~1 to be inel~ erein.
Example 3 Release of Zein-Coate~ Clarithromycin: PolvvinylpvlTolidone Pa~ticles as a Function of Time.
To a solu~on in which sodium bicarbonate (50 mg/5 cc) was dissolved, 125 mg/5 cc of claIi~hrornycin ac~vity (accounting for potency of the active agent and ~he particles), was added, shaken and observed for release of active agent as a func~ion of ~ 12 6 2 n PC~/US92/11011 ~0 93/12771 v ~I
time. Samples were withdrawn, filtered, and measured at 0,4, 24, 72, and 196 hours. ~e samples were filte~ed to remove the suspended partic~es and dle clear fils~e was analyzed for cl~illu~ ycin conten~ The resul~s, as shown in Table 2, below, inslit.~te th~t ve~y low levels of ac~ve drug are released over prolonged periods of ~me.
T~ble 7 Re~ease of Zeitl-CQated C~ wnlyci~ 'olyvillyl~ lidone Pardcles as a l;unction ~Time.
Tim~ (hours) ~0n (~cg/ml~ Pe~en~ ~o o ~0 ' 0 4 ~50 0.24 24 99 0.40 72 118 0.47 19~ 102 0.4 lExamD1e 4 Formulation ~Zein-Coated Clan~ yc;r Zein~oated c~in, com~ iO~o coa~ng was form follows:
~;C~t Amount per dose (5cc) Coa~d cl~i~ ycin260. mg (125 mg activi~) Sucrose 3000. mg ~nth~n gum 73 mg Silica(:3el 10.0 mg Pot~si~ orbate 20.0 mg Bubble Gum Flavor 14.0 mg Sodi~m Bicarbonate 50.0 mg To~als: 3361.5 mg/5 mL ~lnal volume WO 93/12771 PCI /US92/1 101~-2 i~ 6 ~ ~xam~le 5 Bioavaila~ility of Zein-Coated Cl~stlslulsly~;in The bioav~ fy of zein~oated c~ cin~ form~ eA as described in F.~m~le 4, was con~lctç~l in a beagle dog model using an single s~ss~ver design.The study co~d siIlgle dose immPAi~te release tablets c~ 125 mg of daLi~ ~yci~ acti~ to the microc~rslllçs of cl~ill ycin ~ed as ~ in Example 1, abo~e, and ~orm~ e~l as descn~ in PY~mrle 4, above. Th~ r~leasc of cla~ .;in was ~le ~-onci~ ~s~l by a 5~DsS over ~ - of the bioaY~ bili~y Of dle fo~ in a beagle dog model ~ ~ to a ~abletl~~~ ce ~r~ same.
The cross over design allowed d e same d~gs to receive bodl ~ ~~n coa~ed cla~ ~y~ s~ olt as well as dle ~ y~ er~ abl~ ~f the same dose ~125 mg cl~i~ n~eil~ ac~ty)O The results, illus~ d in ~e 1, non~ e ~at ~e ~in~oated cl~;~on~Ll s~.sp~n~ioll did not rele~e ~he cla~ e suspension ~as shown by a ~ep ~,s~r~ e suspension in Example 3, Table 2), but rapidly released dle ac~ve drug in the ga~oi~ siil-~l trac~ of dle dog for eql~ivalent absorption to that ~f dle l~;f~ ce table~
Example 6 Flavor Evalua~ion of Zein-Coated Cl~ ycin Colllp~ te flavor ev~ Qn no~ng characteris~cs of bitterness of ~le particle~coa~ed cla~ ycin and cl~;~ ycin in solu~on was con~ c~3 lhe fo~ula~on used was tha~ descnbed in Example 4~ and was compared with ~: cl~i~i,ulllycin in solu~on as a re~erence standard for the level of bitterness observed for ~e s~np1es. The study was conducted using trained flavor specialis~ whv :~
standardize their palate with ~e use of references which were, in this case, dlesolutions of cld~ ycin. The study CC~n~i~ts of swirling a dose of the matenal, -:
solution or suspended forrnulation, in the mouth and th~n ~ing bittemess, relative to standards, as a ~nc~on of time after tasdng it. The period of time after tasting is evaluated in the event that particles remain or get lodged in the oral cavity be~ore being removed by salivaly secre~ions.
The dose response for the clarithromycin in solu~on can be seen in Figure 2 and the corresponding level of response ~or the suspension is shown ;n Figure 3, as a '~'0 93~1~771 2 1 2 6 2 0 0 37C~/US92tl 1~
func~ion of ~ime after tasting, to demonstrate the lack of bitterness of this forrnulation.
Figure 3 thus shows that levels of free clarithromycin available ~or interaction with easte buds are below 15 ppm even after 7 days in suspension,dlus demonstrating the taste rnz~kin~ abili,~y ~f the zein coa~ng ~r an example of a very bit:ter ph~ e~ ally-ac~ve agent.
Al~ough ~e invention has been exemplilq~d in ~ecirlc Inr~i~r~1iQns~ the details are no~ to be construed as limit~ion~ r it ~ be ay~ar~nt daat va~ious esluivalents, changes and .nc~ c~1~0ns may be e~loyed without d~parting from the~iIit and sco~e the~o~, it being un~le~stood ~at such ~quivalen~ ts are int~.n~1~1 to be inel~ erein.
Claims (19)
1. An orally-administered medicament comprising (a) a core of a pharmaceutically-active agent or nutritional having a surface, and (b) overlaying said surface, an outer polymeric coating comprising a prolamine fraction of grain proteins and a low-to-moderate molecular weight plasticizing agent for said prolamine, wherein the ratio of prolamine to plasticizing agent is from about 40:1 to about 20:3.
2. A medicament according to claim 1, wherein the low-to moderate weight plasticizing agent is a water-insoluble vegetable source oil or wax.
3. A medicament according to claim 1 or 2, wherein the ratio of the pharmaceutically-effective agent or nutritional to the outer polymeric coating is from 20:1 to 1:1 and the outer polymeric coating is from about 1 to about 35 micrometers thick.
4. A medicament according to claim 1, 2 or 3, wherein the prolamine fraction is zein or gliadin, or a mixture thereof, and said prolamine fraction has been purified to 88-96%.
5. A medicament according to claim 1, 2, 3 or 4, which is in the form of a chewable tablet or microcapsular suspension.
6. A medicament according to claim 1, 2, 3, 4 or 5, wherein said pharmaceutically-active agent or nutritional comprises an antibiotic, vitamin, dietary fiber, analgesic, nutritional, enzyme or hormone.
7. A medicament according to claim 6, wherein said pharmaceutically-active agent or nutritional is a macrolide antibiotic.
8. A medicament according to claim 7, wherein said macrolide antibiotic is clarithromycin or erythromycin.
9. An orally consumable liquid comprising an active substance in particle form contained in a liquid suspension, each particle comprising a core containing a pharmaceutically active agent or nutritional, said core being encapsulated by a single coating layer of from about 1 to about 35 micrometers thick wherein the weight ratio of said active agent or nutritional to said coating layer is from 20:1 to 1:1, said coating consisting essentially of a prolamine and a low to moderate weight plasticizing agent, the taste of the active agent or nutritional being masked by said coating layer substantially preventing the dispersion of the active agent or nutritional into the suspension while being readily disintegrated by human gastric juices such that the active agent or nutritional is released therein, the ratio of prolamine to plasticizing agent being from 40:1 to 20:3.
10. The orally consumable liquid of claim 9, wherein said liquid suspension has a pH of about 6.8.
11. The orally consumable liquid of claim 9 or 10, wherein said coating layer comprises 5% to 100%, by weight, based on the weight of the core.
12. The orally consumable liquid of claim 11, wherein said coating layer comprises 45 to 75%, by weight, based on the weight of the core.
13. The orally consumable liquid of claim 9, 10, 11 or 12, wherein the plasticizing agent is present in a weight basis between 2.5 and 25% relative to said prolamine.
14. The orally consumable liquid of claim 9, 10, 11, 12 or 13, wherein said plasticizing agent is a water-insoluble vegetable source oil or wax having a fatty acid chain length of about six to twenty-two carbon atoms.
15. The orally consumable liquid of claim 9, 10, 11, 12, 13 or 14, wherein the active agent or nutritional is selected from the group consisting of analgesics, antibiotics, hormones, vitamins, antihistamines, decongestants, anti-inflammatory agents, hypnotics, sedatives, tranquilizers and antibacterials, enzymes and nutritional supplements.
16. The orally consumable liquid of claim 15, wherein said agent or nutritional is selected from the group consisting of clarithromycin and erythromycin.
17. The orally consumable liquid of claim 15, wherein said active agent or nutritional comprises dietary fiber or amino acids.
18. The orally consumable liquid of any one of claims 9 to 17, wherein the prolamine is selected from zein, gliadin or mixtures thereof.
19. The orally consumable liquid of any one of claims 9 to 17, wherein the prolamine is zein.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US81545891A | 1991-12-31 | 1991-12-31 | |
US815,458 | 1991-12-31 |
Publications (2)
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CA2126200A1 CA2126200A1 (en) | 1993-07-08 |
CA2126200C true CA2126200C (en) | 1998-10-20 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002126200A Expired - Fee Related CA2126200C (en) | 1991-12-31 | 1992-12-18 | Prolamine coatings for taste-masking orally-administrable medicaments |
Country Status (7)
Country | Link |
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EP (1) | EP0620730B1 (en) |
AU (1) | AU661753B2 (en) |
CA (1) | CA2126200C (en) |
DE (1) | DE69231472T2 (en) |
IL (1) | IL104093A (en) |
MX (1) | MX9207559A (en) |
WO (1) | WO1993012771A1 (en) |
Families Citing this family (10)
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TW271400B (en) * | 1992-07-30 | 1996-03-01 | Pfizer | |
JPH10108630A (en) * | 1996-10-04 | 1998-04-28 | Showa Sangyo Co Ltd | Lustering coating agent for food having good workability at the time of coating |
WO1998026766A1 (en) * | 1996-12-18 | 1998-06-25 | Fractales Biotech | Biodegradable capsule with a prolamin base |
AU738512B2 (en) | 1997-10-03 | 2001-09-20 | Lavipharm Laboratories, Inc. | A prolamine-plant polar lipid composition, its method of preparation and applications thereof |
FR2791888B1 (en) * | 1999-04-06 | 2004-10-08 | Ethypharm Lab Prod Ethiques | ORAL PHARMACEUTICAL SUSPENSION |
CN1190185C (en) | 1999-04-06 | 2005-02-23 | 埃迪克埃迪法姆药品实验室 | Drinkable ibuprofen pharmaceutical suspension |
GB2419094A (en) | 2004-10-12 | 2006-04-19 | Sandoz Ag | Pharmaceutical composition of unpleasnt tasing active substances |
AU2015311674B2 (en) | 2014-09-05 | 2018-03-08 | Lupin Inc. | Secnidazole for use in the treatment of bacterial vaginosis |
CN109714985A (en) * | 2016-09-26 | 2019-05-03 | 株式会社山田养蜂场本社 | The enzyme that stable and taste is improved decomposes royal jelly particle |
CN115462493B (en) * | 2022-09-27 | 2023-09-05 | 青岛啤酒股份有限公司 | Composite nano particle based on plant polypeptide encapsulation taste masking and beverage obtained by composite nano particle |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR760403A (en) * | 1932-11-22 | 1934-02-22 | Device for stopping the unwinding of stretched bands | |
FR1323056A (en) * | 1961-03-20 | 1963-04-05 | Marion Laboratories Inc | Method and composition for coating pharmaceutical tablets |
BE622627A (en) * | 1962-10-29 | |||
FR1447175A (en) * | 1964-12-30 | 1966-07-29 | Oreal | New product for coloring bleached hair |
US3497369A (en) * | 1968-07-17 | 1970-02-24 | Corn Products Co | Zein-containing plastic composition |
US3802896A (en) * | 1972-05-15 | 1974-04-09 | Nutrilite Products | Color concentrated base dispersion used in tablet film coating |
US3939259A (en) * | 1974-05-24 | 1976-02-17 | Anthony Pescetti | Coating composition and therapeutic preparation incorporating same |
US4137300A (en) * | 1976-08-20 | 1979-01-30 | Ciba-Geigy Corporation | Sustained action dosage forms |
US4749575A (en) * | 1983-10-03 | 1988-06-07 | Bio-Dar Ltd. | Microencapsulated medicament in sweet matrix |
NZ210785A (en) * | 1984-01-13 | 1987-11-27 | Battelle Development Corp | Liquid dispersions of layered controlled release dosage forms |
BR8506634A (en) * | 1984-12-20 | 1986-09-09 | Rhone Poulenc Sante | COMPOSITES FOR COATING FOOD ADDITIVES INTENDED FOR RUMINANTS AND GRANULATES IN THE FORM OF MICROCAPSULES SO COATED |
WO1991006227A1 (en) * | 1989-11-06 | 1991-05-16 | Opta Food Ingredients, Inc. | Protein-based edible coatings |
-
1992
- 1992-12-14 IL IL10409392A patent/IL104093A/en not_active IP Right Cessation
- 1992-12-18 CA CA002126200A patent/CA2126200C/en not_active Expired - Fee Related
- 1992-12-18 AU AU34159/93A patent/AU661753B2/en not_active Ceased
- 1992-12-18 WO PCT/US1992/011011 patent/WO1993012771A1/en active IP Right Grant
- 1992-12-18 EP EP93902664A patent/EP0620730B1/en not_active Expired - Lifetime
- 1992-12-18 DE DE69231472T patent/DE69231472T2/en not_active Expired - Fee Related
- 1992-12-24 MX MX9207559A patent/MX9207559A/en unknown
Also Published As
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EP0620730B1 (en) | 2000-09-20 |
AU661753B2 (en) | 1995-08-03 |
WO1993012771A1 (en) | 1993-07-08 |
DE69231472T2 (en) | 2001-05-10 |
AU3415993A (en) | 1993-07-28 |
EP0620730A1 (en) | 1994-10-26 |
IL104093A0 (en) | 1993-05-13 |
IL104093A (en) | 1999-06-20 |
EP0620730A4 (en) | 1995-05-17 |
CA2126200A1 (en) | 1993-07-08 |
DE69231472D1 (en) | 2000-10-26 |
MX9207559A (en) | 1994-05-31 |
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